Integrins comprise a large family of cell surface receptors with critical roles in cancer cell proliferation, invasion and metastatic potential. Experiments carried out during the last funding cycle have uncovered a novel pathway of prostate cancer progression mediated by the av?6 integrin. We have found that av?6 is not expressed in human and mouse normal prostate but becomes significantly upregulated in preneoplastic lesions, prostatic adenocarcinoma (AdCa) and bone metastasis. Mechanistically, av?6 expression results in upregulation of androgen receptor (AR) activity via a JNK-mediated pathway. Our findings show, for the first time, that integrins modulate AR activity. In this pathway, we have identified survivin, a bifunctional regulator of cell division and inhibitor of apoptosis, as one of the critical downstream effector molecule which becomes upregulated in cells expressing av?6. Our in vivo data demonstrate that expression of av?6 results in enhanced tumor growth and metastatic dissemination as compared to a different av integrin, av?3. Expression of av?6 also causes tumor-mediated osteolysis, a crucial step in prostate cancer metastasis. Since av?3 has been shown to promote bone gain in prostate cancer metastatic lesions, we hypothesize that the extent of bone-lesion formation is controlled by the relative expression levels of av?6 and av?3. Finally, we show that these integrins'expression is regulated by two different transcription factors activated by TGF?: av?6 is induced via Smad3 activation, whereas av?3 expression is mediated by Runx2. We have formulated a unifying hypothesis that av?6 integrin functions as an integrator of multiple signaling pathways to promote early and late phases of prostate cancer progression. This hypothesis will be tested in the present renewal application by the following aims.
In Aim 1, the molecular mechanisms by which av?6 activates AR will be investigated.
In Aim 2, we will investigate in vivo the role of av?6 in prostate cancer progression in a mouse model of prostate cancer;for this purpose, we will use the prostate specific Pten-null mouse model which develops PIN, cancer and metastasis.
In Aim 3, to credential av integrins as molecular targets in prostate cancer bone lesion therapies, we will dissect the pathways by which av?6 and av?3 contribute to bone disease in vivo. Our long-term objective is to take advantage of this newly generated knowledge to develop novel molecular antagonists of prostate cancer progression.

Public Health Relevance

Studies carried out during the last cycle have uncovered a key role of the av?6 integrin in early and late stages of prostate cancer progression. We will dissect in the present application the pathways by which av?6 enhance tumorigenesis and metastatic bone disease. In parallel, we plan to perform an in vivo study to investigate whether an antibody to av?6 inhibits tumor progression in a mouse model of prostate cancer, Ptenpc-/-. This preclinical study in Ptenpc-/- mice, if successful, will pave the way for a clinical study which may help selecting patients with PTEN mutations {which represent approximately 50% of prostate cancer patients in the US} as the target patient population for av?6 inhibitors. The pathways described in the present application are relevant to the human disease since prostate cancer accounts for a significant cancer burden in USA, where in 2008 it was projected to result in over 28,000 deaths and more than 180,000 new cases. Large gaps still exist in our understanding of disease progression, and this has hampered the development of more effective drugs. New therapeutic approaches in advanced prostate cancer are urgently needed, and harnessing the frequent molecular defects in prostate tumors, such as Pten deficiency, may provide innovative therapeutic opportunities. By inhibiting av?6 - dependent signaling pathways, we will identify critical new approaches suitable for therapeutic intervention and pave the way for personalized therapies of prostate cancer. We will also gain insights in the mechanisms that promote bone metastasis, which is very frequent in prostate cancer patients and which results in severe bone pain, hypercalcemia, nerve compression and pathological fractures. Current treatments, chemotherapies, radiation and bisphosphonates all ameliorate components of the disease, but are not completely effective. Our long-term goal is to take advantage of our mechanistic studies to help develop novel molecular strategies for inhibition of prostate cancer progression in humans.